Phototherapeutical apparatus and method for the treatment and prevention of diseases of body cavities

ABSTRACT

A phototherapeutical apparatus and method are described. The apparatus includes an ultraviolet light source, an optical guidance system, and a patient interface. The patient interface is insertable at least partially into a body cavity and is operable to apply the guided ultraviolet light to a tissue surface of a body cavity. The method includes providing the phototherapeutical apparatus, preparing for the application of the phototherapeutical apparatus, inserting the patient interface at least partially into a body cavity, and applying the ultraviolet light by the patient interface to a tissue surface of a body cavity, wherein the tissue of the body cavity has an inflammatory or a hyperproliferative disease. The inflammatory diseases include rhinitis, sinusitis and rhinosinusitis. A photochemotherapeutical method is also described, using photosensitizing substances, such as psoralen before treatment with ultraviolet light. The phototherapeutical method is also effective for the prevention of inflammatory or hyperproliferative diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/410,690, filed Apr. 9, 2003, which is a continuation of InternationalApplication No. PCT/HU01/00102, filed Oct. 24, 2001, which claimspriority from Hungarian Application No. P0103279, filed Aug. 10, 2001,all of which are incorporated herein by reference.

BACKGROUND

1. Field of the Invention

The present invention relates to the treatment and prevention ofinflammatory and hyperproliferative diseases of body cavities, moreparticularly to the treatment and prevention of diseases of the nasalcavity by phototherapeutical methods.

2. Description of the Related Art

The treatment and prevention of inflammatory diseases of the nasalmucous membrane and paranasal sinuses is an unsolved problem. Thesediseases include allergic rhinitis, commonly referred to as hay fever,vasomotor rhinitis, non-allergic eosinophilic rhinitis, chronicsinusitis, which is the inflammation of the paranasal sinuses, and nasalpolyps.

Rhinitis is an inflammatory disorder of the nasal mucous membrane, whichis characterized by nasal itch, sneeze, nose running, nasal blockage,and rarely by loss of smelling. The inflammation of the nasal mucousmembrane is frequently associated with the inflammation of the paranasalsinuses (rhinosinusitis, chronic sinusitis). As a consequence of thefrequent and persistent inflammation of the mucous membranehyperproliferative lesions, or so-called polyps develop on the mucousmembrane.

One characteristic disease is the allergic rhinitis, commonly referredto as hay fever. The allergic rhinitis is the most frequent allergicdisease affecting 10-20% of the population. The number of patients withallergic rhinitis, especially in the well developed industrial countriesincreased very rapidly in the last few years. Because of the high numberof patients the direct and indirect costs of this disease are great.

Although hay fever is not a very severe disease, its unpleasant symptomsworsen the quality of life considerably. Hay fever is frequentlyassociated with allergic conjunctivitis and sometimes with generalsymptoms. The symptoms last only for a few months in some patients(seasonal rhinitis), while in others they last the whole year (perennialrhinitis).

The symptoms of the allergic diseases develop as follows. An allergenenters the body and induces the production of a specific IgE, whichbinds to specific receptors on the surface of mast cells. Aftersubsequent exposure the allergen crosslinks the IgE receptors, resultingin mediator release from the mast cells. These mediators are responsiblefor the development of the symptoms in patient.

As a result of this activation histamine and other preformed mediatorsare released from the mast cells. In the mast cells new inflammatorymediators are produced attracting further inflammatory cells into themucous membrane (Howarth P H, Salagean M, Dokic D: Allergic rhinitis:not purely a histamine-related disease. Allergy 55: 7-16, 2000).

At present there is no known treatment for rhinitis. The increasednumber of inflammatory cells in the nasal mucous membrane releasemediators, which are responsible for the clinical symptoms. Oftenantihistamines are used locally or systemically for the blocking of thereleased mediators. Sodium cromoglycate is available for the inhibitionof the release of mediators. Finally, corticosteroids are used locallyor systemically for the blocking of the synthesis of new mediators. Inspecial cases a desensitizing therapy might be used. The pathogenesis ofthe development of the clinical symptoms is already well known. However,the presently available drugs often do not eliminate the symptoms.Therefore, every new method for the treatment of this disease has agreat medical significance.

A further characteristic disease is vasomotor rhinitis. Vasomotorrhinitis is an inflammatory disorder of the nasal mucous membrane withunknown origin. The clinical symptoms are largely similar to that ofallergic rhinitis: permanent nasal blockage, nasal itch, sneeze, noserunning, and rarely loss of smelling. Mastocyte-activating mediatorscause the symptoms. These are released from the nerve endings of thenasal mucous membrane upon irritation.

A further characteristic disease is the nonallergic eosinophilicrhinitis. This disease is characterized by the high number ofeosinophils in the nasal secretions and by the lack of an allergicorigin. The disease is frequently associated with the development ofnasal polyps, the hyperproliferative condition of the nasal mucousmembrane. The clinical symptoms are the same as in allergic rhinitis.

Additional diseases are rhinosinusitis and sinusitis. The inflammationof the paranasal sinuses is frequently associated with the inflammatorycondition of the nasal mucous membrane (nasosinusitis). The isolatedinflammation of the paranasal sinuses is also a frequent disease(sinusitis). This disease has often an allergic origin, although itsexact cause remains unknown. There is no well-tested treatment, thususually the same therapy is used as for rhinitis.

Ultraviolet light has been used for more than twenty years for thetreatment of allergic and auto-immune skin diseases. In varioustreatments and procedures ultraviolet-B light (280 nm-320 nm) andultraviolet-A light (320 mn-400 nm) is used typically. The ultravioletlight inhibits the antigen-induced cellular immune response and is ableto induce tolerance (Streilein J W, Bergstresser P R: Genetic basis ofultraviolet-B on contact hypersensitivity. Immunogenetics 27: 252-258,1988).

The ultraviolet light suppresses the immune reaction by inhibiting theantigen presentation and by inducing T-cell apoptosis. Irradiation ofthe skin with ultraviolet-B light or ultraviolet-A light on an areapreviously photosensitized by psoralen is known to inhibit theimmunological processes in the skin. For the treatment of skin diseasesthere are a number of phototherapeutical devices available.

These phototherapeutical devices include ultraviolet light sources.These light sources might be classified based on, for example, theiroperational principle, output energy or power, mode of operation(impulse or continuous), and whether they are emitting monochromatic ormultiwavelength light.

In early treatments broad band ultraviolet B (BB-UVB) light sources wereused. In recent years more efficient narrow band ultraviolet B (NB-UVB)light sources became popular (Degitz K, Messer G, Plewig G, Rocken M:Schmalspektrum-UVB 311 nm versus Breitspektrum-UVB. Neue Entwicklungenin der Phototherapie. Hautarzt 49: 795-806, 1998).

Our previous investigations of psoriatic patients indicated that the 308nm xenon chloride excimer laser is more effective for phototherapeuticaltreatments than the NB-UVB light sources (Bnis B, Kemny L, Dobozy A, BorZs, Szab G, Igncz F: 308 nm UVB excimer laser for psoriasis. Lancet 35:1522, 1997; Kemny L, Bnis B, Dobozy A, Bor Z, Szabo G, Ignacz F: 308-nmexcimer laser therapy for psoriasis. Arch Dermatol. 137: 95-96, 2001).

Phototherapeutical treatments improved significantly with the appearanceof ultraviolet light delivering optical systems. Such an ultravioletlight delivering phototherapeutical system with fiber optic is used inthe Saalmann Cup instrument, in which the concentrated ultraviolet lightis coupled into a fiber optic cable. Therefore, it is suitable for thetreatment of smaller lesions of the skin or mucous membrane (Taube K M,Fiedler H: Hochkonzentrierte UV Bestrahlung kleiner Hautbezirke miteinem neuen Punktstrahler. Grundlagen und klinische Ergebnisse. DeutscheDermatologe, 10: 1453, 1992).

However, the Saalmann Cup can not be introduced into smaller bodycavities because of its large contact area and because of the thicknessof the used fiber optic cable. This device can be used in body cavitieswhere the distal end of the fiber optic cable and the area to be treatedcan be visually controlled, such as the oral cavity. For this reason,this device is unsuitable for the treatment of body areas, which cannotbe visually controlled, such as the nasal and paranasal mucous membrane,the gastrointestinal, and the urogenital mucous membrane.

Although ultraviolet light has been used for the treatment ofhyperproliferative and inflammatory skin diseases for many years, it hasnot been used for the treatment of common, immunologically mediateddisorders of the nasal mucous membrane. Neuman and Finkelstein usednarrow-band, low energy, red-light phototherapy for the treatment of thenasal mucous membrane and they found it effective for perennial allergicrhinitis and for nasal polyposis (Neuman I, Finkelstein Y Narrow-bandred light phototherapy in perennial allergic rhinitis and nasalpolyposis. Ann Allergy Asthma Immunol 78: 399-406, 1997).

There are a number of ultraviolet light delivery systems, which uselasers. For example, the light of the 308 nm xenon chloride excimerlaser can be guided by fiber optic cable for the cleaning of root canalsby ablation (Folwaczny M, Mehl A, Haffner C, Hickel R: Substance removalon teeth with and without calculus using 308 nm XeCl excimer laserradiation. An in vitro investigation. J. Clin. Periodontol 26: 306-12,1999). The 308 nm xenon chloride excimer laser is also suitable to treatartherosclerosis by treating the blood vessel walls (U.S. Pat. No.4,686,979), or to enhance the cardiac oxygenization with transmyocardiallaser revascularisation (U.S. Pat. No. 5,976,124), or inhibitingneovascularisation during angioplasty by destroying myocardial cells(U.S. Pat. No. 5,053,033).

These systems share the common feature that the high-energy ultravioletlight at the end of the light delivering system is focused on smallareas of only a few hundred microns in diameter. This intenseultraviolet light carries out its effect by breaking some of thechemical bonds. However, the intense ultraviolet light damages thetissues with its ablative effect.

It is also known that larger skin lesions can be treated by using anumber of small fiber optic cables (U.S. Pat. No. 6,071,302; WO9607451,Asawanonda P, Anderson R R, Chang Y, Taylor C R: 308-nm excimer laserfor the treatment of psoriasis: a dose-response study. Arch Dermatol136: 619-24, 2000).

Phototherapeutical systems attached to endoscopes are also used for thephotodynamic treatment of tumors, such as bladder carcinoma or bronchialcancer. However, in these instruments no ultraviolet light is used, andthey have special distal ends for tumor treatment (U.S. Pat. Nos.4,313,431; 4,612,938; 4,676,231; 4,998,930; 5,146,917).

At present, the phototherapeutical systems delivering ultraviolet lightconsist of a hand piece specifically shaped to a special problem. Assuch, they are either unsuitable or inconvenient for the treatment ofsmall body cavities such as the nasal cavity with visual control.

Finally, only the light of small concentrated ultraviolet light sourcescan be coupled with good efficiency into thin optical fiber cables,which have a diameter of a few tenth of millimeter. Ultraviolet lasersare suitable for this purpose, but they are expensive.

SUMMARY

Briefly and generally, embodiments of a phototherapeutical apparatus aredescribed, the apparatus including: an ultraviolet light source,operable to generate ultraviolet light, an optical guidance system,operable to receive and guide the ultraviolet light of the light source,and a patient interface, operable to receive the guided light from theoptical guidance system, wherein the patient interface is insertable atleast partially into a body cavity and is operable to apply the guidedultraviolet light to a tissue surface of a body cavity.

Further, embodiments of a method of treating diseases is described. Themethod includes providing a phototherapeutical apparatus, which containsan ultraviolet light source, an optical guidance system, coupled to theultraviolet light source, and a patient interface, coupled to theoptical guidance system. The method further includes preparing for theapplication of the phototherapeutical apparatus, inserting at leastpartially the patient interface into a body cavity, generatingultraviolet light with the ultraviolet light source, coupling thegenerated ultraviolet light into the patient interface through theoptical guidance system, and applying the ultraviolet light by thepatient interface to a tissue surface of a body cavity, wherein thetissue of the body cavity has an inflammatory disease or ahyperproliferative disease.

Examples of inflammatory diseases include the inflammatory diseases ofthe nasal cavity. Research showed that single or repeated irradiation ofthe nasal mucous membrane and paranasal sinuses with ultraviolet lightwith different wavelengths (UVB and UVA) inhibit the clinical symptomsof rhinitis, sinusitis and rhinosinusitis and result the regression ofnasal polyps.

In some embodiments of the phototherapeutical methodphotochemotherapeutical methods are included, such as usingphotosensitizing substances. Psoralen is an example of photosensitizingsubstances.

The phototherapeutical apparatus is also effective for the prevention ofinflammatory diseases or hyperproliferative diseases. In theseembodiments of the method ultraviolet phototherapy is applied before theappearance of clinical symptoms of the disease.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present invention and forfurther features and advantages, reference is now made to the followingdescription taken in conjunction with the accompanying drawings.

FIG. 1 illustrates an embodiment of the phototherapeutical apparatusaccording to the invention.

FIG. 2 illustrates an exemplary implementation of the ultraviolet lightsource according to an embodiment of the invention.

FIG. 3 illustrates an exemplary implementation of the optical couplingunit according to an embodiment of the invention.

FIG. 4 illustrates an exemplary implementation of the patient interfaceaccording to an embodiment of the invention.

FIG. 5 illustrates an exemplary implementation of the patient interfaceaccording to an embodiment of the invention.

FIG. 6 illustrates an exemplary implementation of the patient interfaceaccording to an embodiment of the invention.

FIG. 7 illustrates an exemplary implementation of the patient interfaceaccording to an embodiment of the invention.

FIG. 8 illustrates an exemplary implementation of the patient interfaceaccording to an embodiment of the invention.

FIG. 9 illustrates a phototherapeutical apparatus including a flexibleendoscope, according to an embodiment of the invention.

FIG. 10 illustrates steps of the phototherapeutical method, according toan embodiment of the invention.

FIG. 11 illustrates the decrease of clinical symptoms due to treatmentwith an embodiment of the phototherapeutical method.

FIG. 12 illustrates the decrease of clinical symptoms due to treatmentwith an embodiment of the photochemotherapeutical method.

DETAILED DESCRIPTION

Embodiments of the present invention and their advantages are bestunderstood by referring to FIGS. 1-12 of the drawings. Like numerals areused for like and corresponding parts of the various drawings.

The Phototherapeutical Apparatus

The phototherapeutical apparatus, according to embodiments of thepresent invention is suited for the treatment and prevention of commoninflammatory diseases of the body. In some applications thephototherapeutical apparatus is used for the treatment and prevention ofthe diseases of a nasal mucous membrane and paranasal sinuses such asallergic rhinitis (hay fever), vasomotor rhinitis, nonallergiceosinophilic rhinitis, chronic sinusitis (inflammation in the paranasalsinuses), or nasal polyps with ultraviolet light. In other applicationsthe phototherapeutical apparatus is used for the treatment andprevention of the diseases of a mouth cavity, a throat, an esophagus, astomach, a small intestine, a large intestine, a gastrointestinal tract,a rectum, an ear, a trachea, a urogenital tract, a portio, a uterus, anda conjunctiva.

FIG. 1 illustrates a phototerapeutical apparatus 100, according to anembodiment of the invention. Phototerapeutical apparatus 100 includes aultraviolet light source 1, which generates ultraviolet light beam 2.Ultraviolet light beam 2 enters into an optical coupling unit 3, whereinthe ultraviolet light is focused. The focused ultraviolet light iscoupled by optical coupling unit 3 into an optical guidance system 4.Optical guidance system 4 guides the ultraviolet light into a patientinterface 5. Patient interface 5 is insertable at least partially into abody cavity, where it applies the ultraviolet light to a tissue surfaceof a body cavity. FIG. 1 illustrates an embodiment, where the bodycavity is the nasal cavity and the patient interface is inserted througha nostril 6.

In some embodiments ultraviolet light source 1 generates a continuousultraviolet light, in others a slowly oscillating ultraviolet light. Forexample, in some embodiments the frequency of oscillations can be belowabout 10 Hertz. In various embodiments the continuous ultraviolet lightand slowly oscillating ultraviolet light will be jointly referred to asquasi-continuous ultraviolet light.

Ultraviolet light source 1 can be, for example, a monochromatic lightsource or a multiwavelength light source.

A variety of monochromatic light sources, such as lasers, can be used asultraviolet light source 1, among others xenon chloride laser, nitrogenlaser, frequency multiplied Nd:YAG laser, any solid state laser, xenonfluoride excimer laser, any type of UV diode lasers or other lasersemitting light in the UV spectrum. Multiwavelength ultraviolet lightsources include, for example, discharge lamps, arc lamps filled withxenon, mercury vapour, xenon and mercury vapour, fluorescent lamps, andUV light emitting diodes (UV-LEDs).

The generated ultraviolet light can have a wavelength in theultraviolet-B (280 nm-320 nm) and ultraviolet-A (320 nm-400 nm) part ofthe spectrum.

FIG. 2 illustrates a particular ultraviolet light source 1 according toembodiments of the invention. An electric power supply unit 7 isconnected to electrodes 11 by wires 8. Electrodes 11 enter the internalspace of quartz bulb 12, which is filled with gas. The electric power,provided by electric power supply 7 causes an electric discharge in thegas. During this discharge light is generated. The wavelength of thelight depends, among others, on the chemical composition of the gas.With a suitable choice of the chemical composition of the gas thegenerated light will have a wavelength in the ultraviolet. In someembodiments the gas or gas mixture in quartz bulb 12 can include xenon,argon, and mercury vapour, and any other gas that emit light at leastpartially in the ultraviolet spectrum. Part of the ultraviolet light,generated in the internal space, propagates directly towards focusinglens 15. Other portions of the generated ultraviolet light propagate inother directions. Part of these portions is reflected by concave mirror9 toward focusing lens 15. Focusing lens 15 focuses all incomingultraviolet lights efficiently into an ultraviolet light beam 2. Thefocused ultraviolet light beam 2 leaves housing 10 through an outputopening 14 and reaches an optical filter 13. In some embodiments opticalfilter 13 transmits ultraviolet A, or ultraviolet B, or both types ofrays. From optical filter 13 the filtered and focused ultraviolet lightbeam 2 is coupled into an optical guidance system 4.

The volume of the discharge in quartz bulb 12 varies in the range ofabout 1 mm³ to about tenth of mm³. In some embodiments the dischargevolume is positioned approximately in the focus of concave mirror 9, soconcave mirror 9 can efficiently focus the emitted ultraviolet lightonto focusing lens 15.

FIG. 3 illustrates an embodiment of optical coupling 3. Ultravioletlight beam 2 entering optical coupling unit 3 is directed by a dichroicmirror 16 into optical guidance system 4 through a lens system 17.Dichroic mirror 16 simultaneously performs a spectral filtering ofultraviolet light beam 2.

In some embodiments a targeting light source 18 is employed to guide andassist the application of the ultraviolet light to the intended tissuesurface, as in some embodiments the ultraviolet light beam itself mayhave no component in the visible spectrum. Targeting light source 18 canbe, for example, a HeNe laser or a light diode emitting red light orthat of any other colour. The light of targeting light source 18 alsopasses through dichroic mirror 16, so the targeting light also entersoptical guidance system 4 through lens system 17. In some embodimentsoptical guidance system 4 is also applicable to guide back reflectedlight, reflected from the site of application. The reflected lightpasses dichroic mirror 16 and can be detected through an observingoptical device 19 to assist the application of the phototherapeuticaldevice.

Optical guidance system 4 can be, for example, an optical cable or armsuitable to guide ultraviolet light. The optical cable or arm can beformed of any one of a large number of known suitable materials, amongothers quartz glass or capillary tubes filled with a liquid capable ofguiding ultraviolet light, wherein the internal surface of the capillarytubes are covered with ultraviolet reflecting material. The diameter ofthe optical cable can be between about 1 micron and about 10 mm. In someembodiments optical guidance system 4 also performs the spectralfiltering of ultraviolet light beam 2.

FIG. 4 illustrates an embodiment of patient interface 5, suitable forthe treatment of the nasal mucous membrane and paranasal sinuses.Patient interface 5 is suited to be positioned at least partially in thenostril and guide the ultraviolet light onto the tissue surface to betreated. Many variations of patient interface 5 can be constructed andare meant to be within the scope of the invention.

In the embodiment of FIG. 4 optical guidance system 4 is attached tohandgrip 20. The guided ultraviolet light enters from optical guidancesystem 4 through handgrip 20 into optical tube 22 and propagates into atapered end piece 24. A head 25 of patient interface 5 is coupled tooptical tube 22 by a fastener 23. An illuminating light source 27 isincluded to illuminate the area of the tissue surface to be treated.Illuminating light source 27 is built into handgrip 20, and can bepowered by either an internal or an external power supply unit. Mirror28 reflects the illuminating light of illuminating light source 27 ontothe tissue surface to be treated. The ultraviolet light, theilluminating light, and, if necessary, the targeting light propagatethrough output opening 26 onto the tissue surface to be treated. The endof patient interface 5, where the ultraviolet light leaves patientinterface 5 is sometimes referred to as the distal end. In the presentembodiment the distal end is where output opening 26 is positioned. Amagnifying glass 21 mounted onto patient interface 5 provides visualcontrol of the application of the ultraviolet light ofphototherapeutical apparatus 100.

FIG. 5 shows another embodiment of patient interface 5, wherein theultraviolet light beam 2 enters from optical guidance system 4 through alens 29 of handgrip 20. Ultraviolet light beam 2 is then reflected ondichroic mirror 16, which is mounted inside optical tube 22, and leavespatient interface 5 through output opening 26 of head 25. In thisembodiment illuminating light source 27 is mounted inside handgrip 20.The illuminating light passes through dichroic mirror 16 and isreflected by concave holed mirror 30 to illuminate the tissue surface tobe treated.

In various embodiments external illuminating light sources are appliedto illuminate the tissue area to be treated.

FIG. 6 illustrates another embodiment of patient interface 5. In thisembodiment optical guidance system 4 is coupled into a pen-shapedhandgrip 31. Ultraviolet light beam 2 enters pen-shaped hand grip 31 andis reflected by flat surface treating head 32. Flat surface treatinghead can include, among others, a quartz prism or a flat mirror. Flatsurface treating head 32 is coupled to pen-shaped handle 31 with afastener 23.

FIG. 7 illustrates another embodiment of patient interface 5, which issuitable for the circular treatment of a body cavity, for example, thenasal cavity. In this embodiment optical guidance system 4 guidesultraviolet light beam 2 into pen-shaped grip 31, where it is reflectedby circular reflector 33 in a circular manner. Circular reflector 33 canbe, for example, a conical or a spherical reflecting surface. Circularapplicator head 34, housing circular reflector 33, is coupled topen-shaped handle 31 with fastener 23. Body cavities, such as the nasalcavity can be treated with this embodiment in a circular manner.

FIG. 8 illustrates another embodiment of patient interface 5, which issuited for a spot treatment of tissue surfaces, such as the nasal mucousmembrane. Optical guidance system 4 guides ultraviolet light beam 2 intopen-shaped handle 31, where it is guided onto a spot on the tissue to betreated by spot applicator 36. Spot applicator 36 can be, for example, aplano-parallel disk or a lens 36 made of quartz or plastic transparentto ultraviolet light. Spot applicator 36 is housed by spot applicatorhead 35, which is fastened onto pen-shaped handle 31 by a fastener 23.

FIG. 9 illustrates another embodiment of patient interface 5, which issuited for a spot treatment of tissue surfaces, such as the nasal mucousmembrane. Ultraviolet light beam 2 generated by ultraviolet light source1 is focused and coupled by optical coupling unit 3 into opticalguidance system 4. Optical guidance system is integrated into flexibleendoscope 37. Flexible endoscope 37 is capped with patient interface 5.Patient interface 5 includes a spot applicator 36. Spot applicator 36can be, for example, a plano-parallel disk or a lens 36 made of quartzor plastic transparent to ultraviolet light. In some embodiments spotapplicator 36 can have a sloped distal end.

In order to illuminate the tissue surface to be treated, a illuminatinglight is provided by illuminating light source 27. The generatedilluminating light is guided through lens 41 into illuminating opticalcable 42. Illuminating optical cable 42 can be also integrated intoflexible endoscope 37. The illuminating light illuminates the tissuesurface to be treated through patient interface 5.

Light reflected from the illuminated tissue surface is conducted backfrom the illuminated tissue surface via image processing optical cable38, which can be integrated into flexible endoscope 37 as well. Imageprocessing optical cable 38 is coupled into image processing unit 39 tofacilitate visual control of the application of the phototherapeuticalapparatus.

In some embodiments optical guidance system 4 can be rotated withinflexible endoscope 37 by positioning unit 40, so that the direction ofultraviolet light beam 2 emitted through patient interface 5 can bemodified. In other embodiments flexible endoscope 37 itself can berotated by positioning unit 40. These embodiments are useful for thetreatment of various body cavities, for example, a larynx, a digestivecanal, and urogenital organs.

Some embodiments for the circular and the spot treatment of tissuesurfaces may include a Panoramic Annular Lens (PAL) optical system. APAL system, transparent to the ultraviolet light can be included intocircular applicator head 34 and spot applicator head 35. Including a PALoptical system can be helpful for simultaneous treatment of tissuesurfaces and optical image processing.

Phototherapeutical Method

According to embodiments of the invention, a phototherapeutical method200 is described for the treatment and prevention of inflammatory andhyperproliferative diseases of body cavities, more particularly for thetreatment and prevention of common inflammatory diseases of the nasalmucous membrane and paranasal sinuses, including allergic rhinitis (hayfever), vasomotor rhinitis, nonallergic eosinophilic rhinitis, chronicsinusitis (inflammation in the paranasal sinuses), and for the treatmentand prevention of hyperproliferative diseases, including nasal polyps (afrequent benign hyperproliferative lesion in chronic inflammatoryconditions of the nasal mucous membrane).

Phototherapeutical method 200 is based on the inventor's researchresults, which showed that the application of ultraviolet light ontissue surfaces in body cavities decreases the number and the activityof inflammatory cells (mast cells, eosinophils, and lymphocytes)responsible for the mediator release and synthesis in the mucousmembrane, and thereby it reduces the clinical symptoms of inflammatory,hyperproliferative, and allergic diseases. This effect of theultraviolet light may be partly due to apoptosis induction.

Embodiments of phototherapeutical method 200 can be practiced on variousbody cavities. These body cavities include: nasal cavity, paranasalsinus, mouth cavity, throat, esophagus, stomach, small intestine, largeintestine, gastrointestinal tract, rectum, ear, trachea, urogenitaltract, portio, uterus, and conjunctiva. It is understood that all theseembodiments belong to the scope of the application.

FIG. 10 illustrates steps of phototherapeutical method 200. In step 204phototherapeutical apparatus 100 is provided, wherein phototherapeuticalapparatus 100 includes: ultraviolet light source 1, optical guidancesystem 4, coupled to ultraviolet light source 1, and patient interface5, coupled to optical guidance system 4. Phototherapeutical method 200can be practiced with any embodiment of phototherapeutical apparatus100, described earlier.

In step 204 some embodiments of phototherapeutical apparatus 100 includeessentially monochromatic ultraviolet light sources, other embodimentsinclude multiwavelength ultraviolet light sources. In some embodimentsof phototherapeutical apparatus 100 the monochromatic light source was axenon chloride excimer laser with a wavelength of 308 nm. It was foundthat a 308 nm xenon chloride laser induces dose and time-dependentT-cell apoptosis. Further, it was found that applying a xenon chloridelaser induces the apoptosis of T-cells at a significantly higher ratethan applying a narrow-band UVB (NB-UVB) light.

Other embodiments of phototherapeutical apparatus 100 utilize othermonochromatic ultraviolet light sources, for example, a nitrogen laser,a frequency multiplied Nd-YAG laser, a xenon fluoride excimer laser, anytype of ultraviolet diode lasers, or any other laser, which emits lightin the ultraviolet spectrum.

Yet other embodiments include multiple wavelengths ultraviolet lightsources, for example, discharge lamps and arc lamps. Each of these lampscan be filled, for example, with xenon, mercury vapour, and a mixture ofxenon and mercury vapour. Other embodiments include fluorescent lamps,NB-UVB lamps, ultraviolet light emitting diodes (UV-LEDs), and dyelasers.

In step 206 a preparation for the treatment by phototherapeutical method200 is performed. The preparation can include determining a lightthreshold of the particular patient on a part of the patient's skin,which was not recently exposed to sunlight. One measure of a lightthreshold is the Minimal Erythema Dose (MED). The MED is the smallestdose of ultraviolet light, which causes erythema on the patient'spreviously unexposed skin after 24 hours. The MED is then used todetermine the value of the first dose, applied to the area to betreated.

The preparation can further include selecting a suitable patientinterface 5 for practicing phototherapeutical method 200. This choicedepends, for example, on the location of the area of the tissue surfaceto be treated and the anatomy of the body cavity of the patient.

In step 212 ultraviolet light is generated by ultraviolet light source1.

In step 216 the generated ultraviolet light is coupled into patientinterface 5 through optical guidance system 4.

In step 220 the generated ultraviolet light is applied by patientinterface 5 to a tissue surface of a body cavity. In some embodiments ofthe method, the previously determined MED value is used to determine thefirst dose, applied to the tissue surface to be treated.

In some embodiments of the method, step 220 includes inserting patientinterface 5 at least partially into the body cavity. Patient interface 5is inserted at the distal end.

In some embodiments of step 220, where the tissue surface is the nasalmucous membrane, an ultraviolet light was applied through patientinterface 5 with a dose between about 20 mJ/cm² and about 1000 mJ/cm²,depending on the type of the ultraviolet light source itself. Thetreatment with ultraviolet light can be repeated one or more times perweek. The repeated application of ultraviolet light can be performedwith the same dose or with increasing doses, depending on the patient'stolerance and on the improvements of the clinical symptoms.

Research indicated that the clinical symptoms of the treated nasalmucous membrane improved considerably with the treatment. These symptomsinclude nasal blockage, nasal itch, nose running, sneezing, and itchingof the palate in patients with allergic rhinitis.

FIG. 11 illustrates the improvement of hay fever symptoms of the nasalmucous membrane as a result of being treated by phototherapeutic method200. The illustrated embodiment of method 200 used a 308 nm xenonchloride laser. The severity scores of hay fever (0=no symptoms, 3=verysevere symptoms) are shown before the treatment and after a 3-weektreatment. The treatment included using the same dose twice per week. Asshown, the clinical symptoms and complaints of the patients decreasedsignificantly after the treatment.

Similar improvements were observed in the clinical symptoms of vasomotorrhinitis, nonallergic eosinophilic rhinitis, chronic sinusitis, and inthe sizes of nasal polyps after treatment with phototherapeutical method200. The clinical symptoms decreased considerably after the treatment.

In some embodiments the preparation of step 206 includes increasing theefficacy of phototherapeutical method 200 by administeringphotosensitizing substances before the phototherapy. Sometimes thismethod is referred to as photochemotherapy. An example forphotosensitizing substances is psoralens, including 5-methoxypsoralen,8-methoxypsoralen, and trimethoxypsoralen. These materials can be usedin concentrations between about 0.0005% and about 0.5%, furthermore theycan be applied in creams or in solutions.

When a photosensitizing substance is applied in step 206, the minimalphototoxicitiy dosis (MPD) can be measured on a part of the patient'sskin, which was not exposed to sunlight before starting the therapy. TheMPD is the smallest ultraviolet dose, which induces erythema on apreviously unexposed photosensitized skin after 72 hours.

In step 220 ultraviolet light is applied to the nasal mucous membrane,which was photosensitized with the same photosensitizing substance as instep 206. The application can be started with a dose about 0.1×MPD toabout 5.0×MPD, depending on the severity of the symptoms of the patient.During repeated applications in some embodiments the dose remainsapproximately constant. In other embodiments the dose is increaseddepending on the patient's tolerance. Step 220 can be repeated once orseveral times per week.

Research showed that practicing photochemotherapy through steps 206-220by applying photosensitizing materials inhibits rapidly and effectivelythe clinical symptoms of hay fever, including nasal blockage, nasalitch, nose running, sneezing and itching of the palate.

FIG. 12 illustrates the improvement of hay fever symptoms of the nasalmucous membrane as a result of being treated by photochemotherapeuticmethod 200. This embodiment of the method used a 308 nm xenon chloridelaser. The severity scores of hay fever (0=no symptoms, 3=very severesymptoms) are shown before the treatment and after a 3-week treatment.The treatment was applied twice per week with essentially constantdoses. All the clinical symptoms and complaints of the patientsdecreased substantially after the photochemotherapy.

Similar improvements are observed in the clinical symptoms of vasomotorrhinitis, nonallergic eosinophilic rhinitis, chronic sinusitis, and thesizes of nasal polyps considerably decreased after ultravioletphotochemotherapy.

Phototherapeutical method 200 is also suitable for the prevention ofinflammatory and hyperproliferative diseases of body cavities. Forexample, in the case of seasonal allergic rhinitis phototherapeuticalmethod 200 can be started before the appearance of the clinicalsymptoms. In this embodiment, the prevention is also based on theminimal erythema dose (MED) of the patient and can be administered onceor several times per week.

Similarly, phototherapeutical method 200 with photochemotherapy is alsosuitable for the prevention of the clinical symptoms of patients withseasonal allergic rhinitis. The treatment can be started before theappearance of the symptoms. For prevention, phototherapeutical method200 can be started with doses between 0.1×MPD and 2×MPD, depending onthe severity of the allergy. The treatment can be administered once orseveral times per week depending on the tolerance of the patient.

Finally it is noted that the application of phototherapeutical method200 is significantly cheaper than presently practiced drug basedtreatments.

Potential Side Effects

Ultraviolet light might facilitate the appearance of viral and bacterialinfections on the treated areas because of its immunosuppressive effect.This effect is similar to the effect of topical corticosteroides.However, the likelihood for these infections is lower than that of thepresently used local immuno-suppressive preparations, becauseultraviolet light also has a direct microbicidal effect (Folwaczny M,Liesenhoff T, Lehn N, Horch H H: Bactericidal action of 308 nmexcimer-laser radiation: an in vitro investigation. J Endodontics, 24:781-785, 1998). Furthermore, ultraviolet light also increases the directmicrobicidal activity of epithelial cells (Csat M, Kenderessy Sz A,Dobozy A: Enhancement of Candida albicans killing activity of separatedhuman epidermal cells by ultraviolet radiation. Br J Dermatol 116:469-475, 1987).

Further, it is well known that repeated irradiation by ultraviolet lightin high doses has carcinogenic potency. However, the carcinogenic effectof ultraviolet light is connected with the cumulative dose of theultraviolet light over years. Since the irradiation doses administeredduring phototherapeutical method 200 are much lower than the knowncarcenogenically significant doses, the risk of carcinogenesis is barelyincreased by the present phototherapeutical method 200.

Practicing phototherapeutical method 200 with phototherapeuticalapparatus 100 is further illustrated through the following examples.

EXAMPLE 1

The symptoms of a patient suffering from ragweed-induced hay fever 10years ago did not respond to the used antihistamine and topicalcorticosteroid nasal drops satisfactorily. At examination the patientcomplained of severe nasal blockage, nasal itching, nose running,frequent sneezing and itching of the nasal palate. On an area of theback of the patient, which was not recently exposed to sunlight, theminimal erythema dosis (MED) was determined to be about 200 mJ/cm²,using a 308 nm xenon chloride laser as ultraviolet light source. One daylater the phototherapy of the nasal mucous membrane was started. Forthis purpose ultraviolet light beam 2 of ultraviolet light source 1 wasdirected by optical focusing into optical guidance system 4. Opticalguidance system 4 was an optical cable made of quartz and it had adiameter of 1.6 mm. The optical cable was connected to patient interface5 of the type shown in FIG. 4. Output window 26 of patient interface 5included a plano-parallel transparent plastic disk with a diameter of 4mm. The nasal mucous membrane of the patient was irradiated with a doseof 100 mJ/cm² through output window 26. The irradiation was performedwith a frequency of 1 Hz, wherein the length of the impulses were 15 nsand the energy of one impulse at output window 26 of patient interface 5was 1.79 mJ. Reckoning with the diameter of output window 26 of 4 mm,its surface was 0.1256 cm², so the energy density of the irradiation was14.25 mJ/cm². Altogether seven impulses were administered to provide atotal dose of about 100 mJ/cm². In each nostril 16 areas wereirradiated.

The treatment was controlled visually under protection of ultravioletprotecting glasses using the visible light beam of illuminating lightsource 27 mounted into handgrip 20 of patient interface 5. The completetime of a treatment was 5 minutes, including the time necessary tochange the position of patient interface 5. The treatment did not causeany complaint by the patient. This treatment was repeated two times perweek using the same phototherapeutical apparatus, but the irradiationdose was increased by 50 mJ/cm² weekly. After the second treatment thesymptoms and complaints of the patient decreased to a large extent andin the third week after the sixth treatment the patient was completelyfree of symptoms. The treatment was stopped and no recurrence wasobserved. The treatment was quick and caused no complaint from thepatient. The patient did not receive any drugs during the treatment. Incomparison to the therapies used earlier, phototherapy was found to bemore efficacious by the patient.

EXAMPLE 2

Phototherapeutical treatment was also performed on patients withperennial allergic rhinitis, which was induced by house dust mite andwhose treatment with antihistamine and local steroids proved to beineffective. The phototherapy was performed with xenon chloride excimerlaser of wavelength of 308 nm.

The MED was measured for each patient and phototherapy was started with0.5×MED doses. Circular applicator head 34 for cylindrically symmetrictreatment was inserted into the meatus nasi inferior area of the nasalcavity for the treatment, then a cylindrically symmetric irradiation wasadministered onto the tissue surface with the xenon chloride laser. Thelength of impulses was 15 ns, the frequency of irradiation was 10 Hz.The energy density of each impulse was 2 mJ/cm². The administering ofthe dose of 100 mJ/cm² took 5 seconds. Circular applicator 34 was theninserted into middle and thereafter into the upper part of the nasalcavity and the treatment was repeated in these positions in the sameway. The treatment of the right and left nasal cavities took upapproximately 2 minutes. The treatment was repeated with the same dosestwo times per week. After the eighth treatment the clinical symptoms ofthe hay fever improved considerably at each patient, whereas no sideeffects were observed.

EXAMPLE 3

The severe symptoms of a patient suffering from ragweed-induced hayfever did not improved satisfactorily after using antihistamines andtopical corticosteroid nasal drops. At examination the symptoms (nasalblockage, nasal itching, nose running, frequent sneezing, and itching ofthe nasal palate) of the patient were severe, thereforephototherapeutical method 200 was performed with photochemotherapy. Theminimal phototoxicity dose was measured on the forearm of the patientnot exposed to sunlight. Ultraviolet light source 1 of the type shown inFIG. 2 was used for the irradiation in a way that two ultraviolet lightbeams of wavelengths between 310 and 350 nm were coupled into opticalguidance system 4 through optical filters. The MPD was 500 mJ/cm² andthe treatment of the nasal mucous membrane was started with a dose of2.0×MPD (=1000 mJ/cm²) using patient interface 5 shown in FIG. 4.Photochemotherapy was performed after using 8-methoxypsoralen nasalspray. Head 25 of patient interface 5 shown in FIG. 4 was inserted intothe nasal cavity and the nasal mucous membrane was irradiated with thedose of 1000 mJ/cm². The power density of ultraviolet light beam 2 was43.2 mW/cm² through output window 26 of patient interface 5. Thetreatment was visually controlled under protection of ultravioletprotecting eyeglasses using the visible light beam of illuminating lightsource 27.

Patient interface 5 was brought into contact with the nasal mucousmembrane altogether in eight positions in each nostril. The treatment ofthe nostrils took approximately 3 minutes and caused no complaints fromthe patient. This photochemotherapy was repeated once per week. Thesymptoms of the patient improved considerably after the second treatmentalready and after the third treatment the patient was completely free ofsymptoms. The treatment was stopped after the fourth treatment. Afterthe therapy the symptoms of the patient did not return.

EXAMPLE 4

A patient had a large polyp in the left nostril, which did not improveafter administering local corticosteroids. The polyp caused chronicsinusitis, therefore phototherapeutical method 200 was performed with axenon chloride laser. The minimal erythema dose (MED) was determined onthe back of the patient, which proved to be 250 mJ/cm². For the purposeof phototherapy ultraviolet light beam 2 of wavelength of 308 nm wascoupled into optical guidance system 4 after focusing. Optical guidancesystem 4 was a quartz ultraviolet light conducting cable of diameter 0.5mm. Optical guidance system coupled ultraviolet light beam 2 intopatient interface 5 of the type shown in FIG. 8. Plano-parallel disk 36of thickness of 2 mm made of transparent plastic of patient interface 5was brought into contact with the surface of the polyp and a round areaof diameter 2 mm was irradiated with the dose of 750 mJ/cm². Theirradiation was conduced at the frequency of 5 Hz, the length ofimpulses was 15 ns, the energy of impulse was 1.96 mJ. Altogether twelveimpulses were issued to administer an irradiation dose of 750 mJ/cm².Five days after one single treatment the nasal polyp disappeared withoutany scar formation. All complaints of the patient disappeared as well.

EXAMPLE 5

In a patient with chronic rhinosinusitis with unknown origin differentdrugs, including antihistamines, corticosteroids, and antibiotics wereused, but proved to be ineffective. Therefore, phototherapeutical method200 was administered. Ultraviolet light source 1 of the type shown inFIG. 2 was used for the treatment. The minimal erythema dosage (MED) wasfirst determined on the forearm of the patient not exposed to sunlightearlier, then the phototherapeutical treatment of the nasal mucousmembrane was started with a dose of 140 mJ/cm². Plano-parallel disk 36of diameter of 4 mm of the patient interface 5 shown in FIG. 4 wasbrought into contact with the affected mucous membrane and this surfacewas irradiated during the treatment. The treatment was controlledvisually under protection of ultraviolet protecting eyeglasses using thevisible light of illuminating light source 27. Ultraviolet light wasadministered in altogether eight positions per nostril to irradiate theaffected mucous membrane. This phototherapy was repeated several timesper week. After the sixth treatment the symptoms of the patientdecreased considerably, and after the tenth treatment the patient becamefree of symptoms. One month after stopping the therapy the patient wasstill free of symptoms.

Although the present invention and its advantages have been described indetail, it should be understood that various changes, substitutions, andalterations can be made therein without departing from the spirit andscope of the invention as defined by the appended claims. That is, thediscussion included in this application is intended to serve as a basicdescription. It should be understood that the specific discussion maynot explicitly describe all embodiments possible; many alternatives areimplicit. It also may not fully explain the generic nature of theinvention and may not explicitly show how each feature or element canactually be representative of a broader function or of a great varietyof alternative or equivalent elements. Again, these are implicitlyincluded in this disclosure. Where the invention is described indevice-oriented terminology, each element of the device implicitlyperforms a function. Neither the description nor the terminology isintended to limit the scope of the claims.

1. A phototherapeutical apparatus, comprising: a multiwavelength lightsource configured to generate ultraviolet light with a wavelength in therange of about 280 nm to about 400 nm; and a patient interfaceconfigured to receive the ultraviolet light from the multiwavelengthlight source and configured to be inserted at least partially into anasal cavity.
 2. The apparatus of claim 1, wherein the multiwavelengthlight source comprises a source of UVA light.
 3. The apparatus of claim1, wherein the multiwavelength light source comprises a source of UVBlight.
 4. The apparatus of claim 1, wherein the multiwavelength lightsource comprises a source of UVA light and a source of UVB light.
 5. Theapparatus of claim 1, wherein the multiwavelength light source isselected from the group consisting of a fluorescent lamp, an ultravioletlight emitting diode, a dye laser, an arc lamp, and an electricdischarge lamp.
 6. The apparatus of claim 1, wherein the multiwavelengthlight source comprises a quartz bulb.
 7. The apparatus of claim 1,wherein the multiwavelength light source comprises an ultraviolet LED.8. The apparatus of claim 1, wherein the multiwavelength light sourcecomprises electrodes defining a discharge volume of about 0.1 mm³ toabout 1 mm³.
 9. The apparatus of claim 1, wherein the wavelength isabout 308 nm.
 10. The apparatus of claim 1, further comprising a sourceof visible light coupled to the patient interface.
 11. The apparatus ofclaim 1, further comprising a power supply in communication with themultiwavelength light source.
 12. The apparatus of claim 1, wherein themultiwavelength light source provides a dose in the range of about 20and about 1000 mJ/cm².
 13. The apparatus of claim 1, further comprisinga concave mirror configured to reflect at least a portion of theultraviolet light generated by the multiwavelength light source.
 14. Theapparatus of claim 1, further comprising a focusing lens configured tofocus at least a portion of the ultraviolet light generated by themultiwavelength light source.
 15. The apparatus of claim 1, furthercomprising an optical filter configured to filter at least a portion ofthe ultraviolet light generated by the multiwavelength light source. 16.The apparatus of claim 1, further comprising a targeting light sourcecoupled to the patient interface, wherein the targeting light source isconfigured to provide a targeting light.
 17. The apparatus of claim 16,further comprising a dichroic mirror configured to direct at least aportion of the ultraviolet light and the targeting light.
 18. Theapparatus of claim 1, further comprising a handgrip, wherein themultiwavelength light source is coupled into the handgrip.
 19. Theapparatus of claim 1, wherein the patient interface comprises a lens.20. The apparatus of claim 1, wherein the patient interface comprises ahead and a tube and the head is coupled to the tube with a fastener. 21.A phototherapeutical apparatus, comprising: a multiwavelength lightsource configured to generate ultraviolet light with a wavelength in therange of about 280 nm to about 320 nm; and a patient interfaceconfigured to receive the ultraviolet light from the multiwavelengthlight source and configured to be inserted at least partially into anasal cavity.
 22. A phototherapeutical apparatus, comprising: amultiwavelength light source configured to generate ultraviolet lightwith a wavelength in the range of about 320 nm to about 400 nm; and apatient interface configured to receive the ultraviolet light from themultiwavelength light source and configured to be inserted at leastpartially into a nasal cavity.
 23. A phototherapeutical apparatus,comprising: a multiwavelength light source configured to generateultraviolet light with a wavelength in the range of about 310 nm toabout 350 nm; and a patient interface configured to receive theultraviolet light from the multiwavelength light source and configuredto be inserted at least partially into a nasal cavity.
 24. Aphototherapeutical apparatus, comprising: means for generatingultraviolet light with a wavelength in the range of about 280 nm toabout 400 nm; and means for receiving the ultraviolet light from themeans for generating ultraviolet light, wherein said means for receivingthe ultraviolet light is configured to be inserted at least partiallyinto a nasal cavity.